A Common Polymorphism Renders the Luteinizing Hormone Receptor Protein More Active by Improving Signal Peptide Function and Predicts Adverse Outcome in Breast Cancer Patients

Context: Epidemiological and animal studies indicate a carcinogenic role of estrogens in breast tissue. The pituitary gonadotropin LH is an important regulator of estrogen production in premenopausal women, whereas even in women after menopause, 10–25% of ovarian steroid hormone production is LH dependent. Objective: We hypothesized that an LH receptor (LHR) gene variant may affect LHR function and thereby influence disease outcome in breast cancer patients. Design: The association of a polymorphic CTCCAG (Leu-Gln) insertion (insLQ), in the signal peptide encoded by exon 1 of the LHR gene with breast cancer risk, (disease-free) survival, and clinicopathological features was studied in a large cohort of 751 breast cancer patients with complete follow-up. Functional analysis of the insLQ-LHR and non-LQ-LHR (no LQ insertion) was carried out using transfection studies. Results: We found a significant association between the insLQ-LHR and a shorter disease-free survival (hazard ratio, 1.34; confidence interval, 1.11–1.63; P = 0.003). The mechanism of the effect of insLQ on LHR function involves increased receptor sensitivity (insLQ-LHR has a 1.9 times lower EC50 than non-LQ-LHR; P = 0.02) and plasma membrane expression (insLQ-LHR has 1.4 times higher Bmax; P = 0.0006) rendering the insLQ-LHR allele more active. Conclusions: The insLQ polymorphism increases LHR activity, thereby shortening breast cancer disease-free survival, probably by increasing estrogen exposure in female carriers.